1. Field of Invention
The instant invention relates to novel prodrugs of optically pure benzoquinolizine-2-carboxylic acid and pharmaceutical compositions that include the prodrugs. The compounds and compositions of the invention can be used to treat bacterial Gram-positive, Gram-negative and anaerobic infections, especially infections caused by resistant Gram-positive organism and Gram-negative organism, mycobacterial infections and emerging nosocomial pathogen infections.
2. Background of the Invention
Prodrugs are therapeutic agents, which are inactive per se but in vivo they are transformed into therapeutically active parent molecule. Prodrugs provide optimal physicochemical, pharmacokinetic and pharmacodynamic properties. They can be designed to overcome pharmaceutical, pharmacokinetic or pharmacodynamic barriers such as insufficient oral absorption, poor solubility, insufficient chemical stability, unacceptable taste or odor, irritation or pain, inadequate blood-brain barrier permeability, toxicity and marked presystemic metabolism.
For patient convenience most drugs are administered by the oral route. There are significant hurdles confronting the delivery of a drug from the oral route, which often means that all the administered compound does not reach its intended site of action. The extent to which the compound can overcome the hurdles to oral drug delivery and reach the systemic circulation is quantified by the term oral bioavailability.
The chiral fluoroquinolone S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid also known as S(−)-nadifloxacin is described in Japanese patents JP 63,192,753A and JP 05,339,238A. S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid has the potential to be useful as a commercial antibacterial agent, due to its antibacterial activity profile. However S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid sodium salt has a high propensity to cause phlebitis in rats by intravenous route. Also S-(−) -9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid has an aqueous solubility of 0.8-2.0 mg/ml over the pH range 8.0-9.5 at 28° C., thus creating problems in having to formulate the drug as a tablet or capsule, or in making formulations for gavage and parenteral injection. Thus, a suitable entity, which can overcome the above mentioned problems can help in development of a dosage form acceptable for systemic use in humans and animals.
In this direction we have shown that S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L -arginine salt is a broad-spectrum antibiotic, which possesses lower propensity to cause phlebitis in rats by intravenous route as disclosed in PCT application WO 00/68229. The most stable salt form, S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate, is disclosed in PCT application WO 05/023805A1 (and in corresponding U.S. Pat. No. 7,164,023). It is useful to prepare stable pharmaceutical dosage forms, including an aqueous solution. The injectable form is specially suitable for long-term intravenous therapy for treating diseases caused by bacterial infections in view of its favorable aqueous solubility at pH 9.5, its ideal suitability in not causing venous inflammation on repeated intravenous administration, and its safety profile.
However the oral bioavailability of the S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid and S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate has been found to be poor in animals. The poor oral bioavailability of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid is probably due to the inadequate solubility and hence poor in vivo absorption. Whereas poor oral bioavailability of the L-arginine salt of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid is probably due to the propensity of the compound to precipitate in the acidic pH while transiting through the gastric region where the pH is ˜1 to 2.
Thus, prodrugs approach was envisaged to improve the oral bioavailability of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid. Prodrugs of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid are disclosed in our U.S. Pat. No. 6,750,224. The '224 patent discloses two types of prodrugs—the prodrugs at the 2-carboxylic acid and at the 4-hydroxy of the piperidine side chain. The prodrugs disclosed at 4-hydroxy piperidine include amino acid prodrugs. These prodrugs were studied with the aim to develop an oral pharmaceutical composition. The prodrugs of S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid disclosed therein either did not possess optimal features such as adequate solubility across wide pH range which is likely to be present in the alimentary canal, to show substantial prodrug effect or the prodrugs failed to improve oral bioavailability of S-(−)-9-fluoro -6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid as compared to S-(−)-9-fluoro-6,7-dihydro-8-(4-hydroxypiperidin-1-yl)-5-methyl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acid L-arginine salt tetrahydrate. Amongst the amino acid prodrugs, the L-alanine and L-valine prodrugs were also disclosed. Both the prodrugs, possessed limited water solubility (<10 mg/ml). It is generally suggested that inadequate aqueous solubility is an important factor limiting oral bioavailability.
An objective of the present invention is to provide a compound with improved aqueous solubility across a wide pH range with enhanced oral bioavailability, which is likely to be encountered in the alimentary canal.